U.S. patent number 6,821,289 [Application Number 10/396,017] was granted by the patent office on 2004-11-23 for efficacy and safety of photodynamic therapy by multiple application protocols with photosensitizers that show extended tumor retention.
This patent grant is currently assigned to CeramOptec Industries, Inc.. Invention is credited to Volker Albrecht, Hans-Peter Bode.
United States Patent |
6,821,289 |
Bode , et al. |
November 23, 2004 |
Efficacy and safety of photodynamic therapy by multiple application
protocols with photosensitizers that show extended tumor
retention
Abstract
A safer, improved method of photodynamic therapy is provided for
treating diseased, hyperproliferative tissue, including cancer,
psoriasis, and arthritis, using multiple, sequential
administrations of a photosensitizer (PS) prior to irradiation.
Preferred photosensitizers are characterized by being retained in
the diseased tissue for a longer time than in normal tissue. The
interval between administrations is chosen to be of sufficient
duration to allow the PS content of normal tissues to drop to a
basal or negligible level before the next administration and before
irradiation. At that time, the PS content of the diseased tissue is
still high, not less than half of the initial content after the
last PS administration. In this way, PDT with better selectivity
for the diseased tissue is achieved. With sequential PS
administrations, the PS burden on normal tissue can be kept low, so
that side effects can be reduced, for example damage of the skin by
sunlight or bright indoors artificial lighting. The precise
durations between PS administrations and eventual irradiation vary
between treatments, and are determined on an individual basis.
Preferred PS for use with the present invention have a high and
extended localization in tumor tissue. A preferred PS with these
qualities is pheophorbide a.
Inventors: |
Bode; Hans-Peter (Jena,
DE), Albrecht; Volker (Jena, DE) |
Assignee: |
CeramOptec Industries, Inc.
(East Longmeadow, MA)
|
Family
ID: |
32988699 |
Appl.
No.: |
10/396,017 |
Filed: |
March 25, 2003 |
Current U.S.
Class: |
607/88;
128/898 |
Current CPC
Class: |
A61N
5/062 (20130101); A61P 19/02 (20180101); A61P
35/00 (20180101); A61P 43/00 (20180101); A61P
17/06 (20180101); A61N 5/0601 (20130101) |
Current International
Class: |
A61N
5/06 (20060101); A61N 005/06 () |
Field of
Search: |
;607/88-90
;606/3-10 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Cramers et al, "Optimisation of photodynamic therapy: the influence
of photosensitizer uptake and distribution on tumor response", SPIE
1999; 4156: 63-68. .
Cramers et al, "Foscan uptake and tissue distribution in relation
to photodynamic efficacy", British Journ. of Cancer
2003:88:283-290. .
Maeda et al, "Pheophorbide A Phototoxicity and its Application to
Photoradiation Therapy of Cancer", Photomedicine and Photobiology
1987;9:45-49. .
Hajri et al, "Human pancreatic carcinoma cells are sensitive to
photodynamic therapy in vitro and in vivo", British Journ. of
Surgery 1999;86:899-906. .
Aprahamian et al, "Distribution of pheophorbide A in normal tissues
and in an experimental pancreatic cancer in rats", Anti-Cancer Drug
Design 1993;8:101-114. .
Yano et al, "Photodynamic Therapy for Rat Pituitary Tumor in vitro
and in vivo Using Pheophorbide-a and White Light", Lasers in
Surgery & Med. 1991;11:174-182..
|
Primary Examiner: Gibson; Roy D.
Assistant Examiner: Johnson, III; Henry M
Attorney, Agent or Firm: Skutnik; Bolesh J. BJ
Associates
Claims
What is claimed is:
1. A safer, improved, photodynamic-therapeutic method of treatment
of hyperproliferative diseased tissue, including cancers,
psoriasis, and arthritis, comprising the steps of: a. administering
a preselected dose of a photosensitizer formulation, wherein said
photosensitizer is taken up by said hyperproliferative diseased
tissue at a treatment site and preferentially retained in said
diseased tissue over normal, healthy tissue; b. waiting a first
preselected amount of time to allow said photosensitizer to return
to a basal value in normal tissue while remaining elevated in said
diseased tissue; c. administering at least one additional dose of
said photosensitizer to said treatment site after said preselected
first amount of time, wherein another preselected amount of time
elapses between each additional dose to permit reduction of a
concentration of said photosensitizer to a basal value in normal
tissue; and d. irradiating said treatment site after an additional
period of time has elapsed after the finally administered dose.
2. The method according to claim 1, wherein said first dose and
said at least one additional dose are of an equal amount, and
wherein said period of time between each administration and between
a final administration and irradiation is equal.
3. The method according to claim 1, wherein said steps of
administering said photosensitizer are accomplished by a method
selected from the group consisting of intravenous and topical
administration.
4. The method according to claim 1, wherein concentration of said
photosensitizer in normal tissues returns to the same basal value
after each administration, and wherein a concentration of said
photosensitizer in diseased tissue remains elevated, enabling a
further increase by each said administration, so that a ratio of
said concentration of said photosensitizer in diseased tissue to
said concentration of photosensitizer in healthy tissue increases
with each said administration.
5. The method according to claim 4, wherein said basal level is
such that said normal tissue experiences no photodynamic effects
during said irradiation.
6. The method according to claim 4, wherein said basal level is
such that said normal tissue experiences only minor detrimental
photodynamic effects during irradiation.
7. The method according to claim 4, wherein said ratio is at least
40:1.
8. The method according to claim 1, wherein said photosensitizer
ispheophorbide a.
9. The method according to claim 1, wherein said photosensitizer is
a bacteriopheophorbide.
10. The method according to claim 1, wherein said step of
irradiating is accomplished by placing at least one optical fiber
into said treatment area.
11. The method according to claim 1, wherein a concentration of
said photosensitizer in tissue is measured periodically or
continuously.
12. The method according to claim 11, wherein said measurement is
accomplished by a method selected from the group consisting of:
HPLC fluorescence detection; and administration of a preselected
amount of luminescent material with said photosensitizer, followed
by detection of a concentration of said luminescent material in
said tissue and determination of said concentration of said
photosensitizer based on relative amounts of said luminescent
material and said photosensitizer administered.
13. The method according to claim 11, wherein each said period of
time is selected during said treatment to ensure optimal
concentration of said photosensitizer.
14. The method according to claim 1, wherein said preselected dose
and period of time are determined prior to treatment by adding a
step of observing the differential uptake/retention of a selected
photosensitizer in human or animal subjects.
15. A device for multiple photosensitizer administration
photodynamic therapy of hyperproliferative diseased tissue,
including cancer, comprising: a radiation source; means to deliver
radiation from said source to a treatment area; and means to
regulate administration of multiple photosensitizer doses and to
regulate said radiation delivery means based on preselected
parameters; and wherein said parameters comprise the following, a
number of photosensitizer administrations, period of time between
said photosensitizer administrations, and period of time between a
final photosensitizer administration and irradiation.
16. The device according to claim 15, wherein said regulation means
alerts a user when said period of time expires and said
photosensitizer administration is to be performed.
17. The device according to claim 15, further comprising means to
administer photosensitizers to said treatment area.
18. The device according to claim 15, wherein said preselected
parameters further comprise photosensitizer dosage, radiation
power, and duration of radiation.
19. The device according to claim 15, wherein said regulation means
comprises a microprocessor and suitable software.
20. The device according to claim 19, wherein said microprocessor
and suitable software can automatically administer doses of said
photosensitizer and deliver said radiation.
21. The device according to claim 15, further comprising means to
measure a concentration of said photosensitizer in said tissue.
22. The device according to claim 21, wherein said measurement
means can measure said concentration in both healthy and said
diseased tissue.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to photodynamic therapy of malignant tumors
or diseased tissue with enhanced cellular proliferation using
photosensitizing agents that accumulate selectively in the diseased
tissue. In particular, the present invention relates to
time-separated, multiple administrations of photosensitizer to
enhance accumulation of the photosensitizer in diseased tissue to
improve light sensitivity in the diseased tissue (efficacy) and to
enhance the safety for normal tissue.
2. Information Disclosure Statement
Photodynamic therapy (PDT) is a well-known method for treatment of
cancer and other hyperproliferative diseases. Such other
hyperproliferative diseases comprise the skin disease psoriasis, as
well as arthritis, a chronic inflammatory disease of the
joints.
In PDT, a photosensitizer (PS) is applied to the organism and is
expected to accumulate in diseased hyperproliferative tissue to a
greater extent than in normal tissue. This differential
accumulation is due to several factors. In the blood, the PS is
bound to plasma proteins to a varied extent. One of these plasma
proteins is low density lipoprotein (LDL). LDL can be taken up by
tumor cells, or other cells in hyperproliferative diseases to a
higher extent than by normal cells. Therefore, a higher amount of
PS is delivered to tumor cells or other hyperproliferating tissue.
A further factor may be the altered capillary architecture in
malignant tissue, leading to enhanced permeability of the
capillaries. Furthermore, tumor tissue can have a lower pH than
normal tissue. Low pH favors accumulation of PS with carboxylic
groups, because these groups bind protons, thus leading to
uncharged PS molecules that can penetrate biomembranes easier than
charged PS. Another factor is decreased metabolism of the PS in
malignant cells.
Differential accumulation of PS is a highly desirable goal in
developing methods for PDT, because it helps to protect normal
cells and tissues from damage inflicted by irradiation during PDT
or, especially in case of the skin, by normal daylight or indoor
artificial lighting. So far all known PS, when activated, cause
damage to both healthy and diseased cells in their proximity. Thus,
the ability of PS to preferentially accumulate in diseased tissue
versus normal tissue is an important element of a beneficial
treatment by PDT. Ideally, only malignant cells should be destroyed
during PDT. The unaltered function of the surrounding normal,
healthy cells and the continued presence of intact connective
tissue fibers is the basis for good functional and structural (and
in many cases good cosmetic) results with PDT. Absence of
differential PS accumulation would result in the need for selective
irradiation of the malignant cells. This is, however, generally not
possible for a satisfactory treatment. Irradiation of tumors in PDT
must include a safety margin around the tumor to ensure that all
peripheral cancerous cells are destroyed. Furthermore, it is not
possible to limit PDT effects in tissue depth exactly to the tumor.
There, a safety margin is also necessary.
U.S. Pat. No. 4,957,481 describes single or multiple local
administrations of a PS directly into a tumor mass for covering a
larger tumor area. For multiple administrations, each
administration is spatially separated, so that a specific volume of
tissue is exposed to photosensitizers. This patent uses near
simultaneous, spatially-separated, multiple administrations to
establish and maintain a desired level of photosensitizer across a
large volume of diseased tissue to achieve effective PDT treatment.
It does not, however provide guidance to increase sensitivity in
diseased tissue while maintaining or improving safety for normal
tissue.
Another method involving repeated administrations of PS is
described in U.S. Pat. No. 5,298,018, which describes the use of
Photodynamic Therapy (PDT) as an adjunctive or stand alone
procedure for the treatment of cardiovascular disease, specifically
to prevent restenosis by blocking access of growth factor to
binding sites in smooth muscle cells. The method relies on a
pharmacokinetic therapy with or without light therapy, using
physical or chemical interactions between the photosensitizers and
muscle cells to block the binding sites independent of any light
therapy. In this method, a photosensitizer is administered prior to
the surgical or interventional procedure and then readministered
after the procedure to replace photosensitizer which is cleared or
washed out from the cells over time, thus maintaining a
photosensitizer concentration in a level sufficient to block the
binding sites. This method does not address how to improve efficacy
of PDT treatments while maintaining or improving safety for normal
tissue.
A method related to U.S. Pat. No. 5,298,018 is described in U.S.
Pat. No. 5,422,362 to inhibit the development of intimal
hyperplasia following angioplasty procedures. The method consists
essentially of administering a green porphyrin to the subject
concurrent with and following the angioplasty. Radiation activation
of the green porphyrin is not a part of the method. This method
therefore does not address PhotoDynamic Therapy treatments. It thus
does not deal with how to improve efficacy of PDT treatments while
maintaining or improving the safety for normal tissue.
A study of tissue absorption of the photosensitizer Foscan.RTM. was
performed that features a double photosensitizer administration
protocol. [Cramers et al, "Optimisation of photodynamic therapy:
the influence of photosensitizer uptake and distribution on tumour
respopse", SPIE Vol. 4156 (2001), p. 63-67; Cramers et al,
"Foscan.RTM. uptake and tissue distribution in relation to
photodynamic efficiency", British Journal of Cancer (2003) 88,
283-290)] This study is restricted to
meta-tetrahydroxyphenylchlorin (mTHPC), known as Foscan.RTM., and
relates the "pharmacokinetic and pharmacodynamic parameters for the
photosensitiser Foscan to the extent of PDT damage." The
distribution of Foscan in mice was measured after single and double
injections of Foscan and the PDT response of tumor and cancer cells
was measured. It was determined that the change in concentration in
plasma was not significantly different for single and double
injections, nor was the relative concentration in skin and tumor
tissue significantly different after single or double injections.
Thus, these articles demonstrate that essentially multiple
administrations of the photosensitizer Foscan does not change the
PDT effect of Foscan as compared to single administrations.
There is a need for a method to increase the concentration and
selectivity of accumulation of photosensitizers in
hyperproliferative or otherwise diseased tissue, both to increase
the effectiveness of the treatment and more effectively protect
healthy tissue from damage. The present invention addresses this
need.
OBJECTIVES AND BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to provide a photodynamic
therapy treatment for diseased, hyperproliferative tissues
including cancer, psoriasis, arthritis and pre-cancerous lesions,
with improved efficacy and safety.
It is a further object of the present invention to provide a
photodynamic therapy treatment method that produces higher and more
selective concentrations of PS in diseased tissue than is possible
with prior art methods.
Briefly stated, the present invention provides a safer, improved
method for treating diseased, hyperproliferative tissue, including
cancer, psoriasis, and arthritis, using multiple, sequential
administrations of a photosensitizer (PS) prior to irradiation.
Preferred photosensitizers are characterized by being retained in
the diseased tissue for a longer time than in normal tissue. The
interval between administrations is chosen to be of sufficient
duration to allow the PS content of normal tissues to drop to a
basal or negligible level before the next administration and before
irradiation. At that time, the PS content of the diseased tissue is
still high, not less than half of the initial content after the
last PS administration. In this way, PDT with better selectivity
for the diseased tissue is achieved. With sequential PS
administrations, the PS burden on normal tissue can be kept low, so
that side effects can be reduced, for example damage of the skin by
sunlight or bright indoors artificial lighting. The precise
durations between PS administrations and eventual irradiation vary
between treatments, and are determined on an individual basis.
Preferred PS for use with the present invention have a high and
extended localization in tumor tissue. A preferred PS with these
qualities is pheophorbide a.
The above, and other objects, features and advantages of the
present invention will become apparent from the following
description read in conjunction with the accompanying drawing.
BRIEF DESCRIPTION OF FIGURES
FIG. 1 Graphic representation of PS concentration over time in
tumor and normal tissue, for example the skin, during repetitive
administration of pheophorbide a.
FIG. 2 A flow chart of the process for repeated administration of
photosensitizer according to a preferred embodiment of the present
invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Photodynamic therapy (PDT) of malignant tumors in principle has
become a therapeutic option. However, the currently available
approved photosensitizers such as Photofrin and the prodrug 5-ALA
are partly unsatisfactory. This invention describes improvements of
PDT with photosensitizers (PS) that show highly extended retention
in tumor tissue in comparison to normal tissue. It is described how
multiple, sequential administrations of such PS before irradiation
can lead to enhanced PS-in-tumor concentrations in relation to
normal tissue, or, alternatively, can minimize peak PS
concentrations in normal tissue, thus reducing PDT side effects.
This method is also effective for achieving a highly selective
localization of a PS in a tumor or other diseased,
hyperproliferative tissue, to provide a PDT treatment with
relatively few side effects on healthy tissues. The method is thus
a PDT treatment that is safer and more effective than prior PDT
methods.
The present invention is of particular value if the irradiation
during PDT cannot be limited exactly to the diseased tissue, for
example in the case of interstitial PDT of tumors within the body,
where placement of the light delivering fibres may be difficult, or
where irradiation beyond the periphery of the tumor is necessary to
ensure that all diseased cells are destroyed. Increased selectivity
is also valuable for decreasing side-effects because of a lower or
negligible amount of PS that is retained in healthy tissue. This is
important for reducing photosensitization after systemic
application especially of the skin, where the skin becomes
susceptible to damage by sunlight or bright indoor lights for long
periods after treatment. Lower concentrations in healthy tissue
means less damage to healthy tissue both during and after
treatment.
Many PS have a similar rate of accumulation in diseased versus
normal tissue. PS can, however, also display different accumulation
rates in these two types of tissue. This is especially likely if
cellular metabolism of the PS is very much decreased in tumor cells
or cells of otherwise hyperproliferative tissues. The decrease in
tumor cell PS content then would lag behind that of normal cells.
In such a case the difference in PS accumulation between diseased
and normal tissue can be further increased by repetitive
administration of the PS. After the first application of PS, a
period of time is allowed to elapse during which the PS level in
healthy tissues, for example in the skin, reaches a basal or
negligible value. The tumor PS content then is still high. At this
point the second PS administration is performed. The tumor PS
content is increased considerably and remains high in comparison to
the healthy, normal tissue, where the PS content over time returns
to a basal or negligible level again. At that point the PS can be
administered again and the tumor PS content is raised further.
Repetitive administration with a suitable PS, with extended
localization in tumor or other abnormal cells, can be used to
obtain an extraordinarily high content in these non normal cells,
or to obtain an extraordinarily low content in normal, healthy
cells while having concentrations in the diseased tissue adequate
for effect in PDT treatment. In the latter case, for example, the
PS concentration in the skin can be kept low, so that the risk of
skin damage by sunlight or bright artificial light is
diminished.
The PS that are suitable for use with the present invention are
characterized by exhibiting little change in tumor concentration
after normal tissues already have largely eliminated the PS and
have attained a low, basal PS content. An example of a suitable PS
with extended retention in non normal cells, enabling a high
differential accumulation in non normal tissue by repetitive
administration, is pheophorbide a. Pheophorbide a can attain a high
and extended localization in a tumor in comparison with the
surrounding healthy tissue, and is thus suitable for multiple
administration protocols as described here. Another example of a
suitable type of PS is bacteriopheophorbide, which also can attain
a relatively high and extended localization in diseased tissue.
Pheophorbide a is a naturally occurring porphyrin compound that is
derived from Chlorophyll. It is generated from Chlorophyll by
removal of a phytyl side chain and the central Magnesium ion.
Pheophorbide a content remained high in a chemically induced rat
skin tumor up to 48 hours after administration, whereas the
pheophorbide a content of normal skin reached a basal value by 24
hours after administration, amounting to one tenth of the
tumorpheophorbide a content (Maeda et al, "Pheophorbide a
phototoxicity and its application to photoradiation therapy of
cancer", Photomedicine and Photobiology 1987, 9, 45-49). The
pheophorbide a content of a xenografted human pancreatic tumor in
nude mice did not decrease between 4 and 48 hours after
administration, whereas the PS content of the normal skin reached a
low basal value after 24 hours (Hajri et al, "Human pancreatic
carcinoma cells are sensitive to photodynamic therapy in vitro and
in vivo", British Journal of Surgery 1999, 86, 899-906). The
pheophorbide a content of normal pancreas reached a low constant
value after 24 hours while the content of a pancreatic tumor
remained elevated for at least 48 hours (Aprahamian et al,
"Distribution of pheophorbide a in normal tissues and in an
experimental pancreatic cancer in rats", Anti-Cancer Drug Design
1993, 8, 101-114). The pheophorbide a content of a rat pituitary
tumor decreased slowly during 6 hours after administration while
the content of normal pituitary gland reached a basal value after 4
hours (Yano et al, "Photodynamic therapy for rat pituitary tumor in
vitro and in vivo using pheophorbide a and white light", Lasers in
Surgery and Medicine 1991, 11, 174-182).
In a preferred embodiment, a PS formulation is administered
intravenously, although more localized administrations are
contemplated. For example, for treatments such as skin tumors or
psoriasis, the administrations described herein can be accomplished
topically, where the PS can be incorporated into a cream or
ointment and rubbed onto the affected area. Generally, the benefits
of the present invention (improved efficacy and safety) are
greatest for PS formulations administered intravenously or orally.
However, although topical administration generally allows for
greater specificity in administering PS, the present invention also
improves the effectiveness of topical PDT. For example, it is often
desirable to apply PS to an area greater than the area of the
tumor, to ensure that any undetected diseased cells or areas are
exposed and taken up by photosensitizers. In many prior art PDT
applications, this increases the risk of damaging healthy tissue.
The present invention, because of the resulting high specificity
and low concentration of PS in healthy tissue at the time of
irradiation, allows for application over a larger area without
causing significant damage to healthy tissue.
The interval between administrations of PS is chosen so as to allow
the PS content in normal tissue to drop to a basal value before the
next administration and before eventual irradiation. A basal value
means a value from where a further decrease in the PS content is
much slower than the initial decrease after administration, and
preferably where the tissue damage by the irradiation performed
during PDT is negligible. At that time, the PS content of the
diseased tissue still must be high, for example not less than half
of the initial content after the last PS administration. In this
way, a PDT with better selectivity for the diseased tissue is
achieved. With sequential PS administrations, the PS concentration
in normal tissue can be kept low, so that side effects can be
reduced, for example damage of the skin by sunlight or bright
indoors artificial lighting.
Before beginning PDT with a multiple administration protocol, the
proper dose to be administered must first be chosen. The dose will
vary according to parameters such as tissue type, disease, and
photosensitizer used, and is limited by side effects that occur
when the concentration of the PS after administration reaches its
peak in healthy tissues. The dose is also limited by the PS uptake
capacity of the tumor or other diseased tissue.
Next, the proper time interval between doses is chosen. This
interval must be of a sufficient length to allow the PS
concentration in healthy tissues to return to low or negligible
levels. These levels should be low in comparison to the peak PS
concentrations in these tissues, for example less than 20% of the
peak concentration. Furthermore, the interval should be such that
the concentration does not drop further considerably, for example
not more than 50% during the following 24 hours. In other words,
the interval should cease at a point where the photosensitizer
concentration in healthy tissue is low and where the decrease in
concentration has substantially leveled off. The PS level in a
healthy tissue that is irradiated during a PDT should be
negligible, so that the normal tissue experiences only minor
detrimental photodynamic effects during photodynamic therapy. Such
minor detrimental effects would be those effects to the normal
tissue that are acceptable to a treating physician. In an example
by analogy, minor detrimental effects can be seen in dermatological
observations of minor sunburn, which results in reddening of the
skin and eventual tanning, in contrast to more severe sun damage
that could be accompanied by blistering or permanent toxic
effects.
In some cases, an interval can be chosen where the PS level in
irradiated healthy tissue is below a threshold for photodynamic
effects, so that no effects occur at all in healthy tissue during
irradiation. The PS concentration in irradiated healthy tissue
should preferably attain a level that is below such a
threshold.
After the suitable interval is chosen and has passed, a second dose
of PS is administered. A third administration of the PS should be
performed, if desired, when the PS content in healthy tissues, for
example in that surrounding the diseased tissue, has returned to
the same level as just before the second PS administration. If this
does not happen, the third administration should at least be
performed when PS concentration is at a low level in healthy
tissues. In one example, the PS concentration at the time of the
third administration should not be greater than 150% of the
concentration in healthy tissue just before the second
administration. The interval between the second and third PS
administration should be chosen to allow for development of a
significantly increased difference in PS content between diseased
and healthy tissues For example, the difference in PS concentration
in diseased and healthy tissue should be at least 50% higher than
the difference just before the third PS administration. In the
embodiment where pheophorbide a is the photosensitizer, a typical
administration interval is 24 hours.
The administration can be repeated several times, preferably
resulting in at least a 40:1 ratio of PS concentration in diseased
tissue to PS concentration in healthy tissue.
These pharmacokinetic parameters of photosensitizer dose and
interval between photosensitizer administration can be determined,
for example, with a suitable animal model and can be confirmed in
human studies. When treating tissues like the skin or epithelial
surfaces of some internal organs, measurements of PS tissue levels
can also be performed in individual patients, for example by
fluorescence measurements with an optical fiber.
Where this is not possible, for example in the case of tumors
within the body that will be treated with interstitial light
delivery, suitable parameters for a multiple PS administration
protocol are obtained from animal experiments, using a suitable
model of the tumor to be treated.
In many preferred embodiments, the time period between
administrations, the time period between final administration and
irradiation, and each dose of PS will remain constant. There may,
however, be instances where the time periods or dosage are varied,
whether due to inconsistent absorption or reduction of PS in the
tissue or for other reasons. These variables are determined based
on the individual treatment to obtain an optimal concentration in
diseased tissue and an optimal PS concentration ratio. Instances
where variable time periods or doses could be useful are those
instances where constant or periodic measurement of the PS
concentration is feasible.
Methods of determining PS concentration are established and can be
easily employed with the present invention. For example,
photosensitizers are known that exhibit fluorescence at certain
wavelengths and in certain percentages of concentrations.
Application of fluorescence-exciting radiation can quickly reveal
the concentration of PS in different body areas. Alternatively, a
relatively small amount of luminescent molecules could be included
in the administration. For example, photosensitizers in plasma can
be detected by High Performance Liquid Chromatography (HPLC)
fluorescence detection, and PS concentration can be determined in
skin with a light conducting device and a fluorimeter that when put
onto the skin measures reflected light.
A treatment system for regulating multiple PS administration PDT
treatments is also provided in the present invention. The system
comprises a radiation source and a delivery device to apply
radiation to a treatment area, a regulation device to monitor the
treatment and preferably control the activation of radiation so
that irradiation occurs at a predetermined time based on entered
protocols, and optionally an administration device to administer
photosensitizers systemically or topically.
In a preferred embodiment, the regulation device is in the form of
a desktop computer connected to the radiation source or a
microprocessor system, with suitable software, as part of the
radiation source. Such a system would also feature a display screen
and input keyboard to display the treatment process and provide
information about the treatment. Prior to treatment, proper dosage
levels, number of administrations, and intervals between
administrations and irradiation are determined. This information is
then entered into the control device. A first administration is
performed and the administration is automatically detected or the
user indicates to the control device that the first administration
has been performed. After the predetermined interval, the control
device can alert the user that the second administration is due,
upon which the user performs the second administration. This
continues until the last administration is performed. After the
predetermined interval, the control means activates the radiation
source and performs the irradiation according to previously entered
protocols.
In another embodiment, the control device features a safety shutter
that prevents activation of the radiation source prior to
expiration of the prescribed time period. This feature provides
added safety by ensuring that no radiation is applied before the
photosensitizer concentration in healthy tissue is at a low or
basal, and thus protects healthy tissue from damage due to
inadvertent radiation. In another preferred embodiment, especially
in systemic administrations and in treatments where the interval
between administrations is relatively short, the control device may
automatically administer the photosensitizer instead of a user.
Suitable radiation delivery devices are known in the art and
numerous devices exist that can be coupled to the radiation source.
Such delivery device include, but are not limited to, optical
fibers with or without diffuser tips, optical fiber probes and
non-coherent lamps. Administration devices include syringes for
systemic administration that may be usable by a medical
practitioner or connected to the control device for automated PS
administration.
FIG. 1 illustrates preferred intervals between administration of
doses of pheophorbide a in cancerous tissue. As is shown in the
figure, upon a first administration the concentration of
pheophorbide a is initially high and slowly decreases. The
concentration in healthy tissue quickly decreases and levels off,
where at 24 hours the concentration in healthy tissue is very low
and has reached a point where the concentration decreases very
slowly. After the first 24 hour interval, the concentration in the
tumor is 17 times that in healthy cells. The same effect is
observed after the second administration of pheophorbide a. As a
result, after a total of four administrations and a total time of
96 hours, the concentration of pheophorbide a in healthy tissues
remains very small, and the concentration in the tumor is greater
by a factor of 68.
Once the proper number of doses have been administered after the
chosen intervals, the treatment area is exposed to radiation of a
wavelength suitable to activate the photosensitizer. The manner of
providing radiation is not limited, and will vary depending on the
type and location of treatment. Examples of radiation sources
include high power lamps, diode lasers, light emitting diodes, and
other sources of coherent and non-coherent light. Because of the
greater selectivity of photosensitizer concentration in the present
invention, the area of irradiation need not be restricted strictly
to a tumor area. This is an additional benefit in that any diseased
or cancerous cells that are around the periphery can be destroyed
without significantly harming surrounding healthy tissue, thus
increasing the effectiveness of the treatment and helping to
prevent reoccurrence of the disease.
The present invention is further illustrated by the following
examples, but is not limited thereby.
EXAMPLE 1
PDT of a Pancreas Carcinoma.
A formulation of the PS pheophorbide a is administered
intravenously 4 times as described above, with doses ranging from
approximately 2 to 20 mg of PS per kilogram of body weight,
achieving an at least a 50:1 ratio of PS content in the carcinoma
to the PS content in the surrounding healthy pancreatic tissue.
Light guiding fibres are placed within the tumor under imaging
guidance. The tumor is irradiated with an energy density sufficient
to necrotize the diseased tissue, preferably 100-200 J/cm.sup.2, at
a power density of approximately 100 mW/cm.sup.2. The surrounding
tissue remains intact since the photosensitizer concentration in
that tissue remains under the threshold for photodynamic effects
upon irradiation.
EXAMPLE 2
PDT of a Skin Tumor in a Patient That is Non-Compliant with Skin
Light Protection Measures.
PS administration is split over four administrations so that after
each administration only a small peak PS concentration in the
normal skin is reached, achieving a better light tolerance.
Having described preferred embodiments of the invention with
reference to the accompanying drawings, it is to be understood that
the invention is not limited to the precise embodiments, and that
various changes and modifications may be effected therein by those
skilled in the art without departing from the scope or spirit of
the invention as defined in the appended claims.
* * * * *